Preparation of primary thioamides from nitriles using sodium hydrogen sulfide and diethylamine hydrochloride

Article abstract of DOI:10.1080/00397910500377099

Primary thioamides are prepared in moderate to excellent yields by treating nitriles with sodium hydrogen sulfide and diethylamine hydrochloride in an appropriate solvent with mild heating. Copyright Taylor & Francis LLC.

Full text of DOI:10.1080/00397910500377099

Synthetic Communicationsw, 36: 295–298, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500377099
Preparation of Primary Thioamides From
Nitriles Using Sodium Hydrogen Sulfide
and Diethylamine Hydrochloride
Mark L. Boys and Victoria L. Downs
Department of Chemistry, Pfizer Global R&D, Ann Arbor,
Michigan, USA
Abstract: Primary thioamides are prepared in moderate to excellent yields by treating
nitriles with sodium hydrogen sulfide and diethylamine hydrochloride in an appropriate
solvent with mild heating.
Keywords: Diethylamine hydrochloride, nitrile, sodium hydrogen sulfide, thioamide
Primary thioamides are an important class of molecules, which have found
wide use within the synthetic organic chemistry community. In particular
they are useful intermediates in the preparation of sulfur-containing hetero-
cycles such as thiazoles.[1] Consequently there is a wide body of literature
regarding the production of primary thioamides, which vary in the precursors
and the reagents employed.[2] The most common substrate employed is a
nitrile. Examples of reagents are phosphorus decasulfide and sodium
sulfide,[3] thioacetic acid,[4] O,O-dialkyl dithiophosphates,[5,6] diphenylphos-
phinodithioic acid,[7] ammonium sulfide,[8] and sodium trimethylsilanethio-
late.[9,10] The most common method involves the addition of hydrogen
sulfide to a nitrile.[11] A base, either organic or inorganic, is usually
employed in either catalytic or stoichiometric quantity. Although effective
Received in the USA July 28, 2005
Address correspondence to Mark L. Boys, Department of Chemistry, Pfizer
Global R&D, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. E-mail:
mark.l.boys@pfizer.com
295

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M. L. Boys and V. L. Downs
for the conversion of most aromatic nitriles, this method is not very efficient
for the conversion of nonactivated aliphatic nitriles. It had been reported that a
combination of a secondary amine and a polar aprotic solvent such as N,N-
dimethyl formamide (DMF) was an effective medium for the conversion of
aliphatic nitriles to thioamides using hydrogen sulfide.[12] This method,
although reasonably effective, suffers from several drawbacks. The use of
the toxic and obnoxious (stench) hydrogen sulfide is required, and the stoichi-
ometry of this gaseous reagent is difficult to control. In addition the isolation
of low-molecular-weight or water-soluble thioamides from the DMF on
workup can be problematic.
We report herein a variation on this method, which utilizes a mixture of
the solid reagents sodium hydrogen sulfide hydrate and diethyl amine
hydrochloride in either DMF or a mixture of 1,4-dioxane and water as
solvent (Scheme 1). The need for gaseous hydrogen sulfide is eliminated
and accurate control of reagent stoichiometry is readily achieved. For
thioamides with some aqueous solubility the use of the water/1,4-dioxane
solvent system simplifies product isolation, which can be carried out via
exhaustive extraction with ethyl acetate. Aromatic and activated nitriles are
rapidly converted in high yield. Nonactivated aliphatic nitriles are converted
more slowly, and an excess of reagents is required to help drive the reaction
toward completion, especially with hindered nitriles such as t-butyl nitrile
(Table 1).
GENERAL REACTION PROCEDURE
Nitrile (75 mmol), water (40 mL), 1,4-dioxane (40 mL), sodium hydrogen
sulfide hydrate (225 mmol; caution, toxic!), and diethyl amine hydrochloride
(225 mmol) (6 eq. of reagents used for t-butyl nitrile) were added to a three-
necked, round-bottomed flask equipped with a thermometer, a magnetic
stirrer, and nitrogen inlet. The solution was then heated to 558C until GC,
LC/MS, or TLC showed that conversion was maximal (in the case of
aliphatic nitriles conversion was not always complete). The reaction was
allowed to cool, water (200 mL) was added, and the product was either
isolated by filtration or extracted with ethyl acetate (6 Â 75 mL). The
combined extracts were dried over magnesium sulfate, and the solvent was
1
evaporated. The product was characterized by H NMR and 13C NMR. In
most cases the product was of sufficient purity to use directly. If required
Scheme 1.

Preparation of Primary Thioamides from Nitriles
297
Table 1. Conversion of nitriles to thioamides
Time
(h)
Yield
(%)
Entry
Nitrile
Solvent
DMF
1
2
nC11H22CN
C2H5CN
72
48
58a
76
Dioxane/water
Dioxane/water
Dioxane/water
3
4
42
3
97
85
6
7
Dioxane/water
Dioxane/water
96
6
56a
98
8
Dioxane/water
6
98
9
Dioxane/water
6
91
50
10
DMF
48
aYield following purification.
the product could be purified either using flash chromatography or
recrystallization.
Samples of thioamides prepared in Table 1 were analyzed as follows.
1. Mp 86.58C (ethanol); lit.[13] 82–838C. Microanalysis: Found C, 66.11;
H, 11.77; N, 6.35. C12H25NS requires C, 66.91; H, 11.70; N, 6.50.
2. Mp 40.68C (hexane/ether); lit.[12] 40–438C. Microanalysis: Found C,
40.52; H, 8.05; N, 15.55. C3H7NS requires C, 40.41; H, 7.91; N, 15.71.
3. Mp 131.08C (ether); lit.[12] 1148C. Microanalysis: Found C, 47.17; H,
6.84; N, 13.64. C3H7NS requires C, 47.49; H, 6.97; N, 13.84.
4. Mp 64.48C (ether); lit.[12] 62–658C. Microanalysis: Found C, 34.21; H,
6.66; N, 13.11. C3H7NOS requires C, 34.27; H, 6.71; N, 13.32.
5. Mp 96.98C (ethanol); lit.[7] 96.5–97.58C. Microanalysis: Found C,
63.14; H, 6.00; N, 9.13. C8H9NS requires C, 63.54; H, 6.00; N, 9.26.

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M. L. Boys and V. L. Downs
6. Mp 124.98C (ethanol/water). Microanalysis: Found C, 59.72; H, 5.96;
N, 7.67. C9H11NOS requires C, 59.64; H, 6.12; N, 7.73.
7. Mp 118.38C (ethanol); lit.[7] 115.5–116.5. Microanalysis: Found C,
61.25; H, 5.06; N, 10.12. C7H7NS requires C, 61.28; H, 5.14; N, 10.21.
8. Mp 221.98C, (ethanol); lit.[14] 230–2318C. Microanalysis: Found C,
55.51; H, 5.11; N, 14.17. C9H10N2OS requires C, 55.65; H, 5.19; N,
14.42.
9. Mp 191.78C (ethanol); lit.[15] 189–1918C. Microanalysis: Found C,
55.05; H, 4.40; N, 7.05. C9H9NO2S requires C, 55.37; H, 4.65; N, 7.17.
10. Mp 116.98C (ethanol/water); lit.[16] 116–1198C. Microanalysis: Found
C, 51.20; H, 9.50; N, 11.87. C5H11NS requires C, 51.24; H, 9.46; N,
11.95.
REFERENCES
´
1. Jagodzinski, T. S. Chem. Rev. 2003, 103, 197–227.
2. Walter, W.; Bode, K.-D. Angew. Chem., Int. Ed. Engl. 1966, 5, 447–461.
3. Brillion, D. Synth. Commun. 1992, 22 (10), 1397–1401.
4. Gauthier, J. Y.; Lebel, H. Phosphorous, Sulfur Silicon Relat. Elem. 1994, 96,
325–326.
5. Yousif, N. M. Tetrahedron 1989, 45 (14), 4599–4604.
6. Pudovik, A. N.; Cherkasov, R. A.; Zimin, M. G.; Zabirov, N. G. Bull. Acad. Sci.
USSR Div. Chem. Sci. 1979, 28, 805–809.
7. Benner, S. A. Tetrahedron Lett. 1981, 22 (20), 1851–1854.
8. Bagley, M. C.; Chapaneri, K.; Glover, C.; Merritt, E. A. Synlett 2004, 14,
2615–2617.
9. Shiao, M. J.; Lai, L. L.; Ku, W. S.; Lin, P. Y.; Hwu, J. R. J. Org. Chem. 1993, 58,
4742–4744.
10. Lin, P. Y.; Ku, W. S.; Shiao, M. J. Synthesis 1992 (12), 1219–1220.
11. Rapaport, E.; Cass, M. W.; White, E. H. J. Am. Chem. Soc. 1972, 94, 3153–3159.
12. Gilbert, E. E.; Rumanowski, E. J.; Newallis, P. E. J. Chem. Eng. Data 1968, 13 (1),
130–131.
13. Ralston, A. W.; Vander Wal, R. J.; McCorkle, M. R. J. Org. Chem. 1939, 4, 68–70.
14. Gardner, T. S.; Wenis, E.; Lee, J. J. Org. Chem. 1954, 19, 753–757.
15. Sakai, T. T.; Rama Krishna, N. Biorg. Med. Chem. 1999, 7, 1559–1566.
16. Edward, J. T.; Derdall, G. D.; Wong, S. C. Can. J. Chem. 1977, 55, 2331–2335.